Process for preparing 5-methyl-4-imidazolecarboxylic acid esters

ABSTRACT

A process for the preparation of 5-methyl-4-imidazolecarboxylic acid esters from acetoacetic acid esters. The products of this process are useful as intermediates for preparing cimetidine.

This invention relates to a process for preparing5-methyl-4-imidazolecarboxylic acid esters from acetoacetic acid esters.The 5-methyl-4-imidazolecarboxylic acid esters which are the products ofthis process are useful as intermediates for preparing histamine H₂-antagonists, for example cimetidine.

Cimetidine, which isN-cyano-N'-methyl-N"-[2-(5-methyl-4-imidazolylmethylthio)ethyl]guanidine,is a histamine H₂ -receptor blocking agent of value as an inhibitor ofgastric acid secretion. Cimetidine is widely used in the treatment ofduodenal ulcers.

This invention also relates to a new compound prepared by the process ofthis invention, that is benzyl 5-methyl-4-imidazolecarboxylic acidester.

Methods of preparing esters of 5-methyl-4-imidazolecarboxylic acids havebeen described. Bohme et al., in Chemische Berichte 91:988-996 (1958),described the preparation of ethyl 5-methyl-4-imidazolecarboxylate bythe reaction of the ethyl ester of α-hydroxyacetoacetic acid withformamide and also by the reaction of ethyl α-chloroacetoacetate withformamide and water. The preparation of the corresponding isopropylester by reacting isopropyl chloroacetoacetate with formamide and waterin the presence of formic acid is disclosed in U.S. Pat. No. 4,146,724.

Durant et al., in U.S. Pat. No. 3,950,333, described the preparation of4-substituted-5-imidazolecarboxylic acid ethyl esters by reaction of anethyl alkanoylacetate with sodium nitrite, reduction of the resultingethyl 2-hydroxyimino-3-oxoalkanoate to give the 2-amino-3-oxo compoundsand treatment of that compound with formamide.

Ertel et al., Liebigs Ann. Chem. 1399 (1974), reported the preparationof 1-hydroxy-imidazoles by the reaction of a 2-hydroxyiminoacetoacetatewith an aldehyde and ammonia.

According to the process of the present invention,5-methyl-4-imidazolecarboxylic acid esters are prepared by the followingprocedure: ##STR1## in which R is lower alkyl having 1-4 carbon atoms orbenzyl.

Preferably, the process of this invention is carried out withoutisolating the two intermediates, i.e. (2) and (3) above. Thus, thepreferred process may be represented as follows: ##STR2##

In the first step of the process of this invention, a lower alkyl esterof acetoacetic acid is reacted with nitrous acid. The nitrous acid ispreferably generated by reacting sodium nitrite with an acid, preferablyacetic acid. This reaction is preferably carried out at reducedtemperature, for example at about 0°-15° C., for about 3-6 hours. Ifisolation of the hydroxyimino intermediate (2) is desired, ethyl acetateis the preferred solvent.

Thereafter, either with or without isolating the hydroxyiminointermediate (2), that intermediate is reacted with formaldehyde and amineral acid for example hydrochloric acid, sulfuric acid or phosphoricacid, preferably hydrochloric acid. It is preferable to add thehydroxyimino compound to the formaldehyde/acid solution, rather than toadd the formaldehyde/acid to the hydroxyimino compound, in order tobetter control the exothermic reaction temperature. In carrying out thereaction in a single vessel, it is preferable to add formaldehyde to thehydroxyimino compound to form a suspension and then add the acid to thesuspension. This reaction to form the diketo compound is preferablycarried out at about 0°-15° C. The resulting mixture containing thediketo compound, i.e. α,β-dioxobutyric acid ester, and formaldehyde istreated with aqueous ammonia to raise the pH to about 3 to 5. Thereaction mixture is held at about 65°-70° C. for about 30-60 minutes,then ammonia is added to neutralize the reaction mixture (pH 7). Coolingand filtering gives the 5-methyl-4-imidazolecarboxylic acid ester.

Good yields of the product are obtained by the process of thisinvention, particularly when the acetoacetate ester used is the ethylester and when the mineral acid used is hydrochloric acid.

The process is quite acceptable environmentally, that is, no extensivetreatment of the effluent is needed to meet environmental requirements.

The 5-methyl-4-imidazolecarboxylic acid esters prepared by the processof this invention may be used to prepare histamine H₂ -antagonists, inparticular cimetidine, by reducing the ester to give the5-methyl-4-hydroxymethylimidazole, reacting the hydroxymethyl compoundwith cysteamine and then reacting the resulting5-methyl-4-[(2-aminoethyl)thiomethyl]-imidazole withdimethyl-N-cyanoimidodithiocarbonate and reacting the resultingN-cyano-N'-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]-S-methylisothioureawith methylamine. These processes are described in U.S. Pat. No.3,950,333. A process for reducing the ester to the hydroxymethylcompound using alkali metal or calcium in liquid ammonia is described inU.S. Pat. No. 4,063,023.

The invention is illustrated by the following examples. The temperaturesindicated therein are ° C.

EXAMPLE 1

To a cold (5°) stirred mixture of 3.9 kg. of ethyl acetoacetate in 2.25liters of glacial acetic acid was added a solution of 2.25 kg. of sodiumnitrite in 3 liters of water over one hour at 0°-15°. The reactionmixture was stirred at 0°-15° for six hours and worked up to give ethyl2-hydroxyimino-acetoacetate (4.57 kg.) in 96% yield.

To a cool (0°-5°) stirred suspension of 53 g. (1.76 m.) ofparaformaldehyde in 172 ml. (2 m.) of 37% hydrochloric acid and 40 ml.of water was added 79.5 g. (0.5 m.) of ethyl 2-hydroxyimino-acetoacetateover 20 minutes at 0°-10°. The mixture was stirred for four hours at0°-5°, then 200 ml. of aqueous ammonia (28%) was added over 20 minutesuntil pH reached 4-5 and the temperature rose to 70° C. The reactionmixture was held at 60°-70 ° for 30 minutes and then 60 ml. of aqueousammonia (28%) was added to pH 7 at 65°-70°. The mixture was cooled to10°, then the product was filtered off and washed with water andisopropanol and dried to give 56 g. (72.7% yield) of ethyl5-methyl-4-imidazolecarboxylate, m.p. 203°-205°, assay 98-100%.

EXAMPLE 2

To a cold (5°) stirred solution of 130 g. (1 m.) of ethyl acetoacetatein 75 ml. (1.3 m.) of glacial acetic acid was added 76 g (1 m.) ofsodium nitrite in 110 ml. of water over one hour at 0-15°. The reactionmixture was stirred for 3-6 hours at 0°-15°. Paraformaldehyde (105 g.,3.5 m.) was added over 10 minutes to the reaction mixture at 0° followedby 517 ml. (6 m.) of concentrated hydrochloric acid added slowly overone hour maintaining the exothermic reaction temperature at 0°-10° byexternal cooling. After 3.5 hours of stirring at 0°-10°, 650 ml. ofaqueous ammonia (28%) was added over 20 minutes and the temperature wasallowed to rise to 70° with pH at 5. The reaction mixture was held at65°-70° at pH 5 for 30 minutes and then 65 ml. of aqueous ammonia (28%)was added until the mixture was neutral. The reaction mixture was cooledto 10° and the solid was filtered off, washed with water and isopropanoland dried to give ethyl 5-methyl-4-imidazolecarboxylate (108.5 g., yield70.4%). Assay: 98.4%.

EXAMPLE 3

To a stirred cold (0°) suspension of concentrated hydrochloric acid (516ml.) and paraformaldehyde (105 g.) was added ethyl2-hydroxyiminoacetoacetate prepared from 130 g. (1 m.) of ethylacetoacetate over two hours maintaining the reaction temperature at5°-15°. After stirring one hour at 5°-15°, aqueous ammonia (28%) wasadded slowly until pH reached 5 and temperature rose to 70° over 35minutes. The reaction mixture was held at pH 5 at 65°-70° for 30 minutesand then aqueous ammonia (28%) was added until the mixture was neutral.The mixture was cooled to 10° and the solid material was filtered offand washed with water and isopropanol and dried to give ethyl5-methyl-4-imidazolecarboxylate, m.p. 204°-206°, yield 61-65%.

EXAMPLE 4

One mole of ethyl 2-hydroxyimino-acetoacetate, prepared from 130 g. (1m.) of ethyl acetoacetate, was added over 75 minutes to a stirredsuspension of 166 ml. (3 m.) of concentrated sulfuric acid and 105 g.(3.5 m.) of paraformaldehyde at 5°-10°. The mixture was stirred at5°-10° for four hours and aqueous ammonia (28%) was added to pH 5 andthe temperature rose to 70°. The reaction mixture was held for 30minutes at pH 5 at 65°-70° and then neutralized with aqueous ammonia(28%). The mixture was cooled to 10°. The solid material was filteredoff, washed with water and isopropanol and dried to give ethyl5-methyl-4-imidazolecarboxylate (yield 50%).

Using phosphoric acid in place of sulfuric acid in the above proceduregave ethyl 5-methyl-4-imidazolecarboxylate in 37% yield.

EXAMPLE 5

To a cold (5°) stirred solution of 58.06 g. (0.5 m.) of methylacetoacetate and 37.5 ml. of glacial acetic acid was added 38 g. (0.55m.) of sodium nitrite in 55 ml. of water over 30 minutes maintaining thetemperature 5°-15°. The reaction mixture was stirred for six hours at10°. Then, 52.5 g. (1.75 m.) of paraformaldehyde was added. Concentratedhydrochloric acid (259 ml., 3 m.) was added over 45 minutes maintainingthe exothermic reaction temperature at 0°-5°. After four hours at 0°-5°,aqueous ammonia (28%) was added to the mixture over 20 minutes to pH 5,temperature 70°. The mixture was stirred at 65°-70°, pH 5 for 30 minutesand then neutralized with aqueous ammonia (28%). The reaction mixturewas cooled to 10° and filtered. The solid material obtained was washedwith water and isopropanol to give methyl5-methyl-4-imidazolecarboxylate (36.4 g., 52% yield).

EXAMPLE 6

To a cold (5°) stirred solution of benzyl acetoacetate (1 mole) inglacial acetic acid (75 ml.) was added sodium nitrite solution (1 molein 110 ml. of water) over one hour at 0°-15°. The resulting suspensionwas stirred at 10° for three hours and then it was added to a stirringsuspension of concentrated hydrochloric acid and paraformaldehyde (3.5mole) at 5°-15° over 1.5 hours. The exothermic reaction was maintainedat 10°-15° by external cooling for 45 minutes. Aqueous ammonia (28%)(525 ml.) was added over 40 minutes to pH 5, temperature 65°-70°. After30 minutes at 65°-70°, the pH was raised to 6.5 and the reaction mixturecooled to 15°. The aqueous layer was decanted off and the residue wastriturated with acetone to give benzyl 5-methyl-4-imidazolecarboxylate,m.p. 203°-205°, 30% yield.

EXAMPLE 7

A 2 liter flask was fitted with an overhead stirrer and a nitrogen inletand charged with 600 ml. of anhydrous ammonia. A dry-ice acetone coolingbath was provided to aid the collection of ammonia and to cool thereaction. After the ammonia was collected, sodium (33 g., 1.435 m.) wasadded in portions and dissolved giving a deep blue color. t-Butanol (25ml., 0.266 m.) was added to this solution.5-Methyl-4-imidazole-carboxylic acid ethyl ester (50 g., 0.32 m.) wasadded portionwise. After addition of the ester, the blue solution wasstirred for five minutes and methanol (100 ml.) was added dropwisecausing the blue color to be discharged after a few ml. had been added.Ammonium chloride (78 g., 1.458 m.) was added in portions. The ammoniawas evaporated and isopropanol (700 ml.) was added to the residue andthe mixture was refluxed for 30 minutes with vigorous stirring. Themixture was cooled to 40° and acidified (pH about 1) with hydrogenchloride gas. Water (10 ml.) was added and the mixture stirred at 50°for 30 minutes. The mixture was filtered and the filter cake washed with200 ml. of warm (40°-50°) isopropanol. The solution was concentrated to100 ml. and diluted with acetone (400 ml.) and ether (100 ml.). Theproduct was collected and dried to give 46.0 g. (96%) of4-(hydroxymethyl)-5-methylimidazole hydrochloride.

A solution of 4-hydroxymethyl-5-methylimidazole hydrochloride (30.0 g.)and cysteamine hydrochloride (23.0 g.) in acetic acid (200 ml.) washeated under reflux for 10 hours. Following cooling to 15°-20°, thesolid which crystallized was collected and washed with isopropyl alcoholto give 4-methyl-5-[(2-aminoethylthiomethyl]-imidazole dihydrochloride,m.p. 189°-192°.

(a) A solution of 4-methyl-5-[(2-aminoethyl)-thiomethyl]imidazole (17.0g.) and N-cyano-N',S-dimethylisothiourea (11.2 g.) in acetonitrile (500ml.) was heated under reflux for 24 hours. Following concentration, theresidue was chromatographed on a column of silica gel with acetonitrileas eluant and the product obtained was finally recrystallized fromacetonitrile-ether to yieldN-cyano-N'-methyl-N"-[2-((5-methyl-4-imidazolyl)methylthioethyl]guanidine,m.p. 141°-142°.

(b) A solution of 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole (23.4g.) in ethanol was added slowly to a solution ofdimethyl-N-cyanoimidodithiocarbonate (20.0 g.) in ethanol, with stirringat room temperature. The mixture was set aside overnight at roomtemperature. Filtration affordedN-cyano-N'-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]-S-methylisothiourea,m.p. 148°-150°. The filtrate was concentrated under reduced pressure andthe mixture was triturated with cold water and the solid obtained,filtered off and recrystallized twice from isopropyl alcohol/ether toyield further product, m.p. 148°-150°.

A solution of methylamine in ethanol (33%, 75 ml.) was added to asolution ofN-cyano-N'-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]-S-methylisothiourea(10.1 g.) in ethanol (30 ml.). The reaction mixture was set aside atroom temperature for 2.5 hours. Following concentration under reducedpressure, the residue was recrystallized twice from isopropylalcohol/petroleum ether, affordingN-cyano-N'-methyl-N"-[2-((5-methyl-4-imidazolyl)methylthio)ethyl]guanidine,m.p. 141°-143°.

What is claimed is:
 1. A process for preparing a compound of theformula: ##STR3## in which R is lower alkyl having 1-4 carbon atoms orbenzyl, which comprises reacting an acetoacetate of the formula:##STR4## with nitrous acid, reacting the resulting2-hydroxyiminoacetoacetate of the formula: ##STR5## with formaldehydeand a mineral acid, and reacting the resulting α,β-dioxobutyrate of theformula: ##STR6## with aqueous ammonia and formaldehyde at pH of about 3to 5 in which the three steps are carried out without isolating the2-hydroxyiminoacetate and α,β-dioxobutyrate intermediates.
 2. Theprocess of claim 1 in which the 2-hydroxyiminoacetoacetate is reactedwith formaldehyde and hydrochloric acid.
 3. The process of claim 1 inwhich hydrochloric acid is added to a suspension of the2-hydroxyiminoacetoacetate and formaldehyde at about 0°-15°.
 4. Theprocess of claim 1 in which the nitrous acid is generated by reactingsodium nitrite with an acid.
 5. The process of claim 4 in which the acidis acetic acid.
 6. The process of claim 4 in which the acetoacetate isreacted with sodium nitrite and acetic acid at about 0°-15°.
 7. Aprocess for preparing a compound of the formula: ##STR7## in which R islower alkyl having 1-4 carbon atoms or benzyl, which comprises reactinga 2-hydroxyiminoacetoacetate of the formula: ##STR8## with formaldehydeand a mineral acid, and reacting the resulting α,β-dioxobutyrate of theformula ##STR9## with aqueous ammonia and formaldehyde at pH of about 3to 5 in which the steps are carried out without isolating theα,β-dioxobutyrate intermediate.